Tramadol, a combination of R and L enantiomers, is a novel analgesic that has a complex pharmacology. Its clinical action is primarily mediated by inhibition of norepinephrine neuronal reuptake by the L enantiomer . However, R-tramadol also inhibits 5-hydroxytryptamine (serotonin, 5-HT) reuptake, facilitates 5-HT release , and activates [micro sign]-opioid receptors . Consistent with these mechanisms, administration of the alpha2-adrenoceptor antagonist yohimbine reduces tramadol-induced analgesia by 89% in healthy volunteers; the addition of naloxone (0.8 mg) obliterates the small residual analgesic effect.1
(1) Desmeules J, Piguet V, Collart L, et al. Yohimbine antagonism as a tool to assess the extent of monoaminergic modulation in analgesic effects: experience with tramadol [abstract]. Experientia 1994;50:A79.
Norepinephrine is a major mediator of central thermoregulatory control. For example, the intraventricular injection of norepinephrine decreases core temperature and metabolic rate in conscious primates. This response was mostly attenuated by pretreatment with the alpha-receptor blocker phentolamine . Subsequent study demonstrated that the effect was largely mediated by alpha2 receptors , which is consistent with the thermoregulatory inhibition produced by clonidine [6,7] and dexmedetomidine . Norepinephrine also has substantial peripheral thermoregulatory actions on both the vascular system  and brown fat metabolism [10,11].
The effects of 5-HT on thermoregulatory control are controversial. This drug causes hypothermia in animals  and humans , which suggests that it inhibits thermoregulatory control. The combined alpha1-adrenergic and 5-HT (1a) agonist urapidil similarly suppresses cold-induced shivering in humans . However, the 5-HT receptor antagonist ketanserin inhibits shivering-a response normally associated with reduced control and hypothermic tendencies . Furthermore, the serotonin syndrome is characterized by extreme hyperthermia .
Opioids that activate [micro sign] receptors, such as alfentanil, slightly increase the sweating threshold and markedly decrease the vasoconstriction and shivering thresholds . In this regard, opioid-induced thermoregulatory inhibition resembles that produced by volatile  and IV  anesthetics. Another opioid, meperidine, decreases the shivering threshold twice as much as the vasoconstriction threshold . This special antishivering activity seems to be mediated by the drug's kappa-receptor activity .
Considerable animal and human data thus suggest that tramadol is likely to impair thermoregulatory control. Available data, however, are insufficient to predict the pattern of thermoregulatory inhibition, much less its magnitude. We therefore tested the hypothesis that tramadol produces a concentration-dependent inhibition of thermoregulatory control. Thermoregulatory responses were characterized by their thresholds (triggering core temperatures). The difference between the sweating and vasoconstriction thresholds-temperatures not triggering autonomic thermoregulatory defenses-was considered the interthreshold range. To independently evaluate the contribution of opioid receptors, we also determined thresholds when tramadol and naloxone were given simultaneously.
With approval of the Committee on Human Research of the University of California-San Francisco, we studied eight male volunteers (age 30 +/- 6 yr; height 174 +/- 6 cm, weight 72 +/- 8 kg). The percentage of body fat was 19 +/- 3. None was obese, taking medication, or had a history of thyroid disease, dysautonomia, or Raynaud's syndrome.
Because the parenteral form of tramadol is not approved by the United States Food and Drug Administration, we administered tramadol HCl tablets (Ortho McNeil, Raritan, NJ) orally . In each case, the initial dose was followed by a smaller maintenance dose. This dose was given shortly after the vasoconstriction threshold had been identified. Volunteers were evaluated on four randomly assigned study days in June and July of 1997. Day 1 was a control day on which no drug was given. On Days 2, 3, and 4, patients received tramadol 100 and 25 mg (small dose), tramadol 200 and 50 mg (large dose), and tramadol 200 and 50 mg plus naloxone, respectively. On Day 4, 1.6 mg of naloxone hydrochloride (Astra, Westborough, MA) was injected over 15 min, followed by a maintenance infusion of naloxone at a rate of 1 mg/h. We did not test naloxone alone because it is known not to alter oxygen consumption . At least 5 days were allowed between treatments, but the interval averaged 10 days.
Volunteers had a light breakfast before arriving at the laboratory but refrained from coffee and tea intake during the 8 h before each investigation. During the study, they were allowed to drink water and to eat crackers. The volunteers were minimally clothed and rested supine on a standard operating room Table in a room maintained at 22-23[degree sign]C. Studies were scheduled so that thermoregulatory responses were triggered at similar times each day. A 14-g catheter was inserted in a right antecubital vein for blood sampling. An 18-g catheter was inserted in a left forearm vein for naloxone or isotonic sodium chloride solution administration.
To minimize redistribution hypothermia , we prewarmed the volunteers for 1 h with a full-body forced-air warmer (Augustine Medical, Inc., Eden Prairie, MN) on "low" and a circulating-water mattress (Cincinnati Sub-Zero, Cincinnati, OH) set at 37[degree sign]C . Fifteen minutes before the end of prewarming, we administered the loading dose of naloxone or isotonic sodium chloride solution placebo. We then administered tramadol, after crushing the tablets and mixing them with applesauce for blinding purpose.
After tramadol administration, we waited 2 h until the peak effect of tramadol was expected . Skin and core temperatures were then gradually increased with forced air and circulating water until significant sweating was observed. Skin and core temperatures were then gradually decreased using the circulating-water mattress and a prototype forced-air cooler. The study ended each day when shivering was detected. Temperature changes were restricted to <3[degree sign]C/h because changes at this rate do not trigger dynamic thermoregulatory responses . The arms were protected from active warming and cooling throughout to avoid locally mediated vasomotion. However, all other skin below the neck was similarly manipulated.
Core temperature was recorded from the tympanic membrane using Mon-a-Therm[registered sign] thermocouples (Mallinckrodt Anesthesiology Products, Inc., St. Louis, MO). Mean skin-surface temperature and cutaneous heat transfer were calculated from measurements at 15 area-weighted sites . Temperatures were recorded at 1-min intervals from thermocouples connected to calibrated Iso-Thermex[registered sign] thermometers (Columbus Instruments Corp., Columbus, OH) with an accuracy of 0.1[degree sign]C and a precision of 0.01[degree sign]C.
Sweating was continuously quantified on the left upper chest using a ventilated capsule . We considered a sweating rate >40 g [center dot] m-2 [center dot] h-1 for at least 5 min significant . Absolute right middle fingertip blood flow was quantified using venous-occlusion volume plethysmography at intervals of 1-5 min . The vasoconstriction threshold was determined post hoc by an observer blinded to treatment and core temperature. As in previous similar studies , we used systemic oxygen consumption to quantify shivering. A DeltaTrac[registered sign] metabolic monitor (SensorMedics Corp., Yorba Linda, CA) was used in canopy mode. PETCO2 was sampled from a catheter inserted into one nostril; gas removed from the catheter for analysis was returned to the canopy of the metabolic monitor. As an index of opioid effect, pupillary reflexes were evaluated using an infrared pupillometer (Fairville Medical Optics, Larkings Green, Amersham, UK) . Pupillary reflex amplitude was measured before drug administration and then at each thermoregulatory threshold.
Peripheral venous blood was sampled before administration of the drug and at the time of sweating, vasoconstriction, and shivering to measure tramadol, o-desmethyltramadol (a pharmacologically active metabolite), and naloxone blood concentrations. The samples were centrifuged and the plasma was frozen at -20[degree sign]C until analysis.
For the analysis of tramadol and o-desmethyltramadol, plasma (1 mL) was alkalinized with 0.05 mL of 25% aqueous ammonia solution in a polypropylene centrifuge tube and extracted into 5 mL of ethyl acetate, along with 0.5 mL of morphine 20 [micro sign]g/mL as the internal standard. The ethyl acetate layer was transferred to a second polypropylene tube and evaporated to dryness under nitrogen at 40[degree sign]C, then reconstituted in 0.2 mL of mobile phase. The mobile phase was 30:70 acetonitrile:10 mM KH2 PO4 and 1 mM sodium dodecyl sulfate, running through a 150 x 3.9 mm Novapak C18 column (Waters Associates, Milford, MA) at 1 mL/min with detection by fluorescence at 235 nm excitation and 295 nm emission. The response was linear to at least 5000 ng/mL, with detection limits of 10 ng/mL and 5 ng/mL and within-day coefficients of variation of 3.9% and 4.8% (n = 10) at 250 ng/mL for tramadol and o-desmethyltramadol, respectively.
The analytical method for naloxone was similar except that 0.025 mL of morphine 20 [micro sign]g/mL was used as the internal standard and detection was electrochemical at 0.85 volts. For naloxone, the response was linear to at least 1000 ng/mL, with a detection limit of 1 ng/mL and a within-day coefficient of variation of 6.6% (n = 10) at 20 ng/mL.
Heart rate and SpO2 were measured continuously using pulse oximetry, and blood pressure was determined oscillometrically at 5-min intervals at the left ankle. Sedation was scored every 15 min (0 = alert, 1 = arouses to voice, 2 = arouses with gentle tactile stimulation, 3 = arouses with vigorous tactile stimulation, 4 = unarousable).
The cutaneous contribution to sweating  and to vasoconstriction and shivering  is linear. We thus used measured skin and core temperatures at each threshold to calculate the core-temperature threshold that would have been observed had skin been maintained at a single designated temperature: Equation 1 where the fractional contribution of mean skin temperature to the threshold was termed beta. We have previously described the derivation and validation of this equation . We used beta = 0.1 for sweating  and beta = 0.2 for vasoconstriction and shivering . The designated skin temperature was set at 34[degree sign]C, a typical intraoperative value.
Ambient temperature and humidity on each study day were first averaged within each volunteer; the resulting values were then averaged among volunteers. Results for each study day were compared using repeated-measures analysis of variance and Dunnett's t-tests. Baseline values were recorded 15 min before thermal manipulations started. Sedation scores were compared using Friedman's test.
From the calculated core temperature thresholds at each dose, tramadol concentration-response curves for the sweating, vasoconstriction, and shivering thresholds were determined in individual volunteers using linear regression. The average slopes and correlation coefficients (r2) for the volunteers in each group were computed from these individual values and compared using repeated-measures analysis of variance. Threshold versus concentration regressions were also computed from the average values from all eight volunteers. All results are presented as means +/- SD. P < 0.05 was considered statistically significant.
Ambient temperatures, relative humidity, and sedation scores were comparable on each of the study days. Even at the largest tramadol dose, the volunteers were only minimally sedated. None of the volunteers became nauseated during the measurement period, but four complained of nausea (without vomiting) during recovery from the large-dose protocol. Tramadol administration had no clinically important effects on hemodynamic responses, respiratory rate, or oxygen saturation (Table 1).
By design, plasma tramadol concentrations differed significantly on the days that patients received small and large doses (approximately 100 and 200 ng/mL, respectively). The concentrations were, however, similar at the sweating, vasoconstriction, and shivering thresholds within each study day. Plasma tramadol concentrations were comparable on the day that patients received large-dose tramadol and naloxone. Tramadol administration produced concentration-dependent increases in the drug's main metabolite, o-desmethyltramadol. For technical reasons, naloxone concentrations were available for only six of the eight volunteers; values were comparable (near 3.5 ng/mL) at each threshold (Table 2).
Tramadol produced a concentration-dependent decrease in the sweating threshold of -1.03 +/- 0.67[degree sign]C[center dot][micro sign]g-1[center dot]mL (r2 = 0.90 +/- 0.12). Tramadol also decreased the vasoconstriction threshold by -3.0 +/- 4.0[degree sign]C[center dot][micro sign]g-1[center dot]mL (r2 = 0.94 +/- 0.98) and the shivering threshold by -4.2 +/- 4.0[degree sign]C[center dot][micro sign]g-1[center dot]mL (r2 = 0.98 +/- 0.98). Because the vasoconstriction threshold was reduced more than the sweating threshold, the sweating to vasoconstriction interthreshold range nearly doubled from 0.3 +/- 0.4[degree sign]C to 0.7 +/- 0.6[degree sign]C during the administration of large-dose tramadol (P = 0.04). Tramadol administration did not significantly alter the vasoconstriction to shivering range. Regressions computed from the average values in all eight volunteers are shown in Figure 1. Adding naloxone to large-dose tramadol had a minimal effect on the sweating and vasoconstriction thresholds but returned the shivering threshold to nearly control values.
There was little evidence of an opioid effect as judged by pupil size or reflex amplitude. The only statistically significant change in pupillary responses was an approximately 1-mm decrease in pupil size during the administration of large-dose tramadol at the shivering threshold. This decrease was fully reversed by naloxone administration (Table 3).
Volatile  and IV  anesthetics, opioids [17,20], and central alpha2 agonists  increase the sweating threshold while decreasing the vasoconstriction and shivering thresholds. Consequently, all these drugs increase the sweating to vasoconstriction interthreshold range approximately 5- to 20-fold .
In contrast to most anesthetics and anesthetic adjuvants, tramadol slightly decreased the sweating threshold. This reduction is consistent with the sweating sometimes observed after tramadol administration . Tramadol also decreased both the vasoconstriction and shivering thresholds, which is consistent with the drug's antishivering effect . The cold response thresholds were reduced linearly with tramadol concentrations, but the magnitudes were modest (approximately 0.6-0.9[degree sign]C). Comparable reductions in the vasoconstriction and shivering thresholds suggests that tramadol does not posses a special antishivering activity similar to meperidine . This is consistent with tramadol's 20:1 [micro sign] to kappa receptor selectivity .
The effects of tramadol most resemble those of midazolam 0.3 [micro sign]g/mL, another drug that slightly decreases the thresholds triggering all three major autonomic thermoregulatory defenses . In this respect, both drugs reduce the "setpoint" rather than produce a generalized impairment of thermoregulatory control. Nonetheless, tramadol decreased the vasoconstriction and shivering thresholds more than the sweating threshold. Consequently, the interthreshold range nearly doubled from a control value of 0.3 +/- 0.4[degree sign]C to 0.7 +/- 0.6[degree sign]C at a plasma concentration near 200 ng/mL. This indicates that tramadol slightly decreases the precision of thermoregulatory control in addition to reducing the setpoint.
Activation of [micro sign]-opioid receptors contributes only slightly to the analgesic action of tramadol [1,2]. Under clinical circumstances, much of the opioid activity results from the main metabolite of tramadol, which binds [micro sign]-opioid receptors far better than the parent compound (W. Reimann, Grunenthal GmbH, Aachen, Germany, personal and written communication, 1996) Nonetheless, pupil size and reflex amplitude, which correlate with analgesia , remained nearly normal during tramadol administration. Furthermore, naloxone 3.5 ng/mL only partially reversed the thermoregulatory actions of tramadol. Only at the shivering threshold on Day 3 was a significant reduction in pupil size observed, and only the shivering threshold was significantly increased by naloxone administration. With the possible exception of shivering, [micro sign] receptor activation thus contributes little to the thermoregulatory effects of tramadol.
Tramadol administration did not produce any clinically important sedation. We also failed to observe any consistent or important hemodynamic alterations, which is consistent with previous reports . Nausea is a known complication of tramadol , and we observed it in half of the patients on Day 3. Nausea, however, was not detected when large-dose tramadol was combined with naloxone, which suggests that nausea may be mediated by the drug's activation of [micro sign]-opioid receptors.
Tramadol has a relatively high oral bioavailability (68%), a long half-life, and is approximately 20% bound to plasma proteins . Consequently, oral loading followed by a maintenance dose produced plasma concentrations that were essentially constant during the hours required for thermoregulatory testing. Tramadol concentrations effective for postoperative analgesia after major abdominal surgery vary greatly and are best described by a log-normal distribution with a median of 288 ng/mL (range 20-986 ng/mL) . A more typical target concentration, however, is near 200 ng/mL . The higher plasma concentrations in this study (approximately 200 ng/mL) was thus a roughly therapeutic dose. We restricted our largest dose to a total of 250 mg to minimize the risk of nausea and vomiting . Presumably, larger doses would produce thermoregulatory impairment greater than we observed. Our study design did not permit independent evaluation of the thermoregulatory effects of tramadol and its major metabolite, but both are normally present during clinical use.
Tramadol decreased the sweating threshold by -1.03 +/- 0.67[degree sign]C[center dot][micro sign]g-1[center dot]mL (r2 = 0.90 +/- 0.12). Tramadol also decreased the vasoconstriction threshold by -3.0 +/- 4.0[degree sign]C[center dot][micro sign]g (-1)[center dot]mL (r2 = 0.94 +/- 0.98) and the shivering threshold by -4.2 +/- 4.0[degree sign]C[center dot][micro sign]g-1[center dot]mL (r2 = 0.98 +/- 0.98). The sweating to vasoconstriction interthreshold range thus nearly doubled from 0.3 +/- 0.4[degree sign]C to 0.7 +/- 0.6[degree sign]C during the administration of large-dose tramadol. The addition of naloxone only partially reversed the thermoregulatory effects of tramadol. The thermoregulatory effects of tramadol most resemble those of midazolam, another drug that slightly decreases the thresholds triggering all three major autonomic thermoregulatory defense. In this respect, both drugs reduce the setpoint rather than produce a generalized impairment of thermoregulatory control. Nonetheless, tramadol nearly doubled the interthreshold range at a concentration near 200 ng/mL. This indicates that tramadol slightly decreases the precision of thermoregulatory control in addition to slightly reducing the setpoint.
We greatly appreciate the assistance of Merlin Larson. We also thank M. Cornelis, Oudenaarde, Belgium, and the Department of Anesthesia, OLV-Hospital, Aalst, Belgium for providing JLDW with a travel grant.
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